Some women respond to even very low doses of progesterone with symptoms of excess. This is not so much an excess susceptibility as an indication that these women's endogenous production is adequate to provide for their needs. In practice, the range of progesterone tolerance can be quite narrow, and a tiny dose is all that is needed to complete the balance between the estrogens and progesterone.

Approximately 30-40% of menopausal women who take progesterone experience unpleasant PMS-like symptoms such as moodiness, irritably, breast tenderness and muscle aches. Individuals who had significant premenstrual symptoms while they were premenopausal are more likely to be affected. Progestins produce moodiness and irritability by effecting specific sites in the brain. Changing the type of progesterone, the dose, the route of administration and the length of treatment can lessen this effect.

It is also possible to experience allergic reactions to HRT preparations. Women who are allergic to peanuts need to be aware that some hormone replacement preparations including Prometrium contain peanut oil and are capable of producing serious allergic reactions in those who are susceptible.